2010 Grants - Zhao

2010 Investigator-Initiated Research Grant

After menopause, a woman's risk of Alzheimer's disease increases. The explanation for this increase in risk is not well understood, but various lines of research suggest that it may be related to declines in estrogen levels or increases in the risk of type 2 diabetes, both of which occur after menopause.

Liqin Zhao, Ph.D. and colleagues have found that a protein known as insulin-degrading enzyme (IDE) may serve as a link between menopause, and the increased risk for Alzheimer's disease. They have found that IDE degrades beta-amyloid, a protein fragment strongly implicated in Alzheimer pathology. Furthermore, the researchers have found that decreased levels of estradiol, such as occurs during menopause, reduce the expression of IDE, potentially reducing the ability of the brain to dispose of beta-amyloid.

Dr. Zhao and colleagues have proposed to study how estrogen regulates levels of IDE in the brain, and how such regulation influences the risk of Alzheimer pathology. The researchers will use mice that have been genetically altered to express different estrogen receptors in order to examine which estrogen receptor controls expression of IDE. They will also test how another gene that affects the risk for Alzheimer's disease, known as ApoE, influences the regulation of IDE levels by estrogen. Finally, using mice genetically altered to express Alzheimer-like pathology, Dr. Zhao's team will test whether treatment of the mice with estrogen increases IDE levels, and whether that effect slows or prevents the development of Alzheimer-like pathology. These studies will advance our understanding of the potential role of estrogen in protecting the brain from disease.